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1.  Mental Paper Folding Performance Following Penetrating Traumatic Brain Injury in Combat Veterans: A Lesion Mapping Study 
Cerebral Cortex (New York, NY)  2012;23(7):1663-1672.
Mental paper folding is a complex measure of visuospatial ability involving a coordinated sequence of mental transformations and is often considered a measure of mental ability. The literature is inconclusive regarding the precise neural architecture that underlies performance. We combined the administration of the Armed Forces Qualification Test boxes subtest measuring mental paper folding ability, with a voxel-based lesion symptom mapping approach to identify brain regions associated with impaired mental paper folding ability. Using a large sample of subjects with penetrating traumatic brain injury and defined lesions studied over 2 time points, roughly 15 and 35 years post-injury, enabled us to answer the causal questions regarding mental paper folding impairment. Our results revealed that brain injury significantly exacerbates the decline of performance on mental paper folding tasks over time. Our study adds novel neuropsychological and neuroimaging support for parietal lobe involvement; specifically the right inferior parietal lobule (Broadmann's Area [BA] 40) and the left parahippocampal region (BAs 19, 36). Both areas were consistently associated with mental paper folding performance and demonstrate that the right parietal lobe and the left parahippocampal gyrus play an integral role in mental paper folding tasks.
doi:10.1093/cercor/bhs153
PMCID: PMC3673178  PMID: 22669970
inferior parietal; left hippocampal gyrus; lesion analysis; mental paper folding; penetrating head injury
2.  Dorsolateral Prefrontal Contributions to Human Intelligence 
Neuropsychologia  2012;51(7):1361-1369.
Although cognitive neuroscience has made remarkable progress in understanding the involvement of the prefrontal cortex in executive control functions for human intelligence, the necessity of the dorsolateral prefrontal cortex (dlPFC) for key competencies of general intelligence and executive function remains to be well established. Here we studied human brain lesion patients with dlPFC lesions to investigate whether this region is computationally necessary for performance on neuropsychological tests of general intelligence and executive function, administering the Wechsler Adult Intelligence Scale (WAIS) and subtests of the Delis Kaplan Executive Function System (D-KEFS) to three groups: dlPFC lesions (n = 19), non-dlPFC lesions (n = 152), and no brain lesions (n = 55). The key results indicate that: (1) patients with focal dlPFC damage exhibit lower scores, at the latent variable level, than controls in general intelligence (g) and executive function; (2) dlPFC patients demonstrate lower scores than controls in several executive measures; and (3) these latter differences are no longer significant when the pervasive influence of the general factor of intelligence (g) is statistically removed. The observed findings support a central role for the dlPFC in general intelligence and make specific recommendations for the interpretation and application of the WAIS and D-KEFS to the study of high-level cognition in health and disease.
doi:10.1016/j.neuropsychologia.2012.05.017
PMCID: PMC3478435  PMID: 22634247
prefrontal cortex; dorsolateral prefrontal cortex; general intelligence; executive function; lesion evidence
3.  Dorsolateral Prefrontal Contributions to Human Working Memory 
Although neuroscience has made remarkable progress in understanding the involvement of prefrontal cortex in human memory, the necessity of dorsolateral prefrontal cortex (dlPFC) for key competencies of working memory remains largely unexplored. We therefore studied human brain lesion patients to determine whether dlPFC is necessary for working memory function, administering subtests of the Wechsler Memory Scale, the Wechsler Adult Intelligence Scale, and the N-Back Task to three participant groups: dlPFC lesions (n = 19), non-dlPFC lesions (n = 152), and no brain lesions (n = 54). DlPFC damage was associated with deficits in the manipulation of verbal and spatial knowledge, with left dlPFC necessary for manipulating information in working memory and right dlPFC critical for manipulating information in a broader range of reasoning contexts. Our findings elucidate the architecture of working memory, providing key neuropsychological evidence for the necessity of dlPFC in the manipulation of verbal and spatial knowledge.
doi:10.1016/j.cortex.2012.05.022
PMCID: PMC3495093  PMID: 22789779
working memory; prefrontal cortex; dorsolateral prefrontal cortex; lesion data
4.  Injured Brain Regions Associated with Anxiety in Vietnam Veterans 
Neuropsychologia  2013;51(4):686-694.
Anxiety negatively affects quality of life and psychosocial functioning. Previous research has shown that anxiety symptoms in healthy individuals are associated with variations in the volume of brain regions, such as the amygdala, hippocampus, and the bed nucleus of the stria terminalis. Brain lesion data also suggests the hemisphere damaged may affect levels of anxiety. We studied a sample of 182 male Vietnam War veterans with penetrating brain injuries, using a semi-automated voxel-based lesion-symptom mapping (VLSM) approach. VLSM reveals significant associations between a symptom such as anxiety and the location of brain lesions, and does not require a broad, subjective assignment of patients into categories based on lesion location. We found that lesioned brain regions in cortical and limbic areas of the left hemisphere, including middle, inferior and superior temporal lobe, hippocampus, and fusiform regions, along with smaller areas in the inferior occipital lobe, parahippocampus, amygdala, and insula, were associated with increased anxiety symptoms as measured by the Neurobehavioral Rating Scale (NRS). These results were corroborated by similar findings using Neuropsychiatric Inventory (NPI) anxiety scores, which supports these regions’ role in regulating anxiety.
In summary, using a semi-automated analysis tool, we detected an effect of focal brain damage on the presentation of anxiety. We also separated the effects of brain injury and war experience by including a control group of combat veterans without brain injury. We compared this control group against veterans with brain lesions in areas associated with anxiety, and against veterans with lesions only in other brain areas.
doi:10.1016/j.neuropsychologia.2013.01.003
PMCID: PMC3644343  PMID: 23328629
anxiety; traumatic brain injury; voxel-based lesion symptom mapping
5.  Preservation of General Intelligence following Traumatic Brain Injury: Contributions of the Met66 Brain-Derived Neurotrophic Factor 
PLoS ONE  2014;9(2):e88733.
Brain-derived neurotrophic factor (BDNF) promotes survival and synaptic plasticity in the human brain. The Val66Met polymorphism of the BDNF gene interferes with intracellular trafficking, packaging, and regulated secretion of this neurotrophin. The human prefrontal cortex (PFC) shows lifelong neuroplastic adaption implicating the Val66Met BDNF polymorphism in the recovery of higher-order executive functions after traumatic brain injury (TBI). In this study, we examined the effect of this BDNF polymorphism on the preservation of general intelligence following TBI. We genotyped a sample of male Vietnam combat veterans (n = 156) consisting of a frontal lobe lesion group with focal penetrating head injuries for the Val66Met BDNF polymorphism. Val/Met did not differ from Val/Val genotypes in general cognitive ability before TBI. However, we found substantial average differences between these groups in general intelligence (≈ half a standard deviation or 8 IQ points), verbal comprehension (6 IQ points), perceptual organization (6 IQ points), working memory (8 IQ points), and processing speed (8 IQ points) after TBI. These results support the conclusion that Val/Met genotypes preserve general cognitive functioning, whereas Val/Val genotypes are largely susceptible to TBI.
doi:10.1371/journal.pone.0088733
PMCID: PMC3935849  PMID: 24586380
6.  BDNF Polymorphism–Dependent OFC and DLPFC Plasticity Differentially Moderates Implicit and Explicit Bias 
Cerebral Cortex (New York, NY)  2011;22(11):2602-2609.
This study examined the role of orbitofrontal cortex (OFC) and dorsolateral prefrontal cortex (DLPFC) plasticity in controlling implicit and explicit social biases. Normal controls and patients with varied OFC and DLPFC lesion size and single nucleotide polymorphisms (SNPs) in the brain-derived neurotrophic factor (BDNF) gene, which promotes (methionine–valine [Met/Val] SNP) or stifles (valine–valine [Val/Val] SNP) plasticity in damaged PFC regions, completed measures of implicit and explicit social bias. Patients and controls demonstrated comparable levels of implicit bias, but patients with Met/Val SNPs exhibited less implicit bias when they had smaller OFC lesions compared with Val/Val patients with similar size lesions and those with large OFC lesions. Both patients and controls demonstrated patterns of explicit bias consistent with hypotheses. Patients with Met/Val SNPs exhibited less explicit bias when they had smaller DLPFC lesions sizes compared with Val/Val patients with similar size lesions and those with large DLPFC lesions. OFC lesion size and BDNF SNP type did not moderate explicit bias; DLPFC lesion size and BDNF SNP type did not moderate implicit bias (nor did other medial or lateral regions). Findings suggest that plasticity within specific PFC regions modulates the type and degree of social bias that individuals’ exhibit.
doi:10.1093/cercor/bhr337
PMCID: PMC3464413  PMID: 22123938
BDNF; implicit and explicit bias; PFC plasticity; social neuroscience; TBI
7.  Damage to the left ventromedial prefrontal cortex impacts affective theory of mind 
Studies investigating theory of mind (ToM) abilities (i.e. ability to understand and predict others’ mental states) have revealed that affective and cognitive functions play a significant role and that each of those functions are associated with distinct neural networks. Cognitive facets of ToM have implicated the medial prefrontal cortex, temporo-parietal junction and the anterior paracingulate cortex, whereas affective facets have implicated the ventromedial prefrontal cortex (vmPFC). Although the vmPFC has repeatedly shown to be critical for affective functions, knowledge regarding the exact role of the left and right vmPFC in affective ToM is still obscure. Here, we compared performances of 30 patients with left, right and bilateral vmPFC lesions to two comparison groups (one without and one with brain injuries) on the Faux Pas Recognition task measuring the facets of ToM. We also investigated whether any deficits may be associated with other emotional measures, namely emotional empathy and emotional intelligence. Our results extend earlier findings by showing that the vmPFC is associated with abilities in affective ToM. More importantly, our results revealed that the left, and not the right vmPFC as indicated previously, is involved in affective ToM and that this deficit is associated with emotional intelligence.
doi:10.1093/scan/nsr071
PMCID: PMC3501703  PMID: 22021651
affective theory of mind; ventromedial prefrontal cortex; traumatic brain injury; emotional intelligence; empathy
8.  Imaging Findings Associated with Cognitive Performance in Primary Lateral Sclerosis and Amyotrophic Lateral Sclerosis 
Introduction
Executive dysfunction occurs in many patients with amyotrophic lateral sclerosis (ALS), but it has not been well studied in primary lateral sclerosis (PLS). The aims of this study were to (1) compare cognitive function in PLS to that in ALS patients, (2) explore the relationship between performance on specific cognitive tests and diffusion tensor imaging (DTI) metrics of white matter tracts and gray matter volumes, and (3) compare DTI metrics in patients with and without cognitive and behavioral changes.
Methods
The Delis-Kaplan Executive Function System (D-KEFS), the Mattis Dementia Rating Scale (DRS-2), and other behavior and mood scales were administered to 25 ALS patients and 25 PLS patients. Seventeen of the PLS patients, 13 of the ALS patients, and 17 healthy controls underwent structural magnetic resonance imaging (MRI) and DTI. Atlas-based analysis using MRI Studio software was used to measure fractional anisotropy, and axial and radial diffusivity of selected white matter tracts. Voxel-based morphometry was used to assess gray matter volumes. The relationship between diffusion properties of selected association and commissural white matter and performance on executive function and memory tests was explored using a linear regression model.
Results
More ALS than PLS patients had abnormal scores on the DRS-2. DRS-2 and D-KEFS scores were related to DTI metrics in several long association tracts and the callosum. Reduced gray matter volumes in motor and perirolandic areas were not associated with cognitive scores.
Conclusion
The changes in diffusion metrics of white matter long association tracts suggest that the loss of integrity of the networks connecting fronto-temporal areas to parietal and occipital areas contributes to cognitive impairment.
doi:10.1159/000353456
PMCID: PMC3776403  PMID: 24052798
Motor neuron disease; Executive function; Diffusion tensor imaging
9.  Screening for C9ORF72 repeat expansion in FTLD 
Neurobiology of aging  2012;33(8):1850.e1-1850.11.
In the present study we aimed to determine the prevalence of C9ORF72 GGGGCC hexanucleotide expansion in our cohort of 53 FTLD patients and 174 neurologically normal controls. We identified the hexanucleotide repeat, in the pathogenic range, in 4 (2 bv-FTD and 2 FTD-ALS) out of 53 patients and one neurologically normal control. Interestingly, two of the C9ORF72 expansion carriers also carried two novel missense mutations in GRN (Y294C) and in PSEN-2 (I146V). Further, one of the C9ORF72 expansion carriers, for whom pathology was available, showed amyloid plaques and tangles in addition to TDP-43 pathology. In summary, our findings suggest that the hexanucleotide expansion is probably associated with ALS, FTD or FTD-ALS and occasional comorbid conditions such as Alzheimer’s disease. These findings are novel and need to be cautiously interpreted and most importantly replicated in larger numbers of samples.
doi:10.1016/j.neurobiolaging.2012.02.017
PMCID: PMC3743244  PMID: 22459598
FTLD; bv-FTD; FTD-ALS; C9ORF72; GRN; PSEN-2; Alzheimer’s disease
10.  An integrative architecture for general intelligence and executive function revealed by lesion mapping 
Brain  2012;135(4):1154-1164.
Although cognitive neuroscience has made remarkable progress in understanding the involvement of the prefrontal cortex in executive control, the broader functional networks that support high-level cognition and give rise to general intelligence remain to be well characterized. Here, we investigated the neural substrates of the general factor of intelligence (g) and executive function in 182 patients with focal brain damage using voxel-based lesion–symptom mapping. The Wechsler Adult Intelligence Scale and Delis–Kaplan Executive Function System were used to derive measures of g and executive function, respectively. Impaired performance on these measures was associated with damage to a distributed network of left lateralized brain areas, including regions of frontal and parietal cortex and white matter association tracts, which bind these areas into a coordinated system. The observed findings support an integrative framework for understanding the architecture of general intelligence and executive function, supporting their reliance upon a shared fronto-parietal network for the integration and control of cognitive representations and making specific recommendations for the application of the Wechsler Adult Intelligence Scale and Delis–Kaplan Executive Function System to the study of high-level cognition in health and disease.
doi:10.1093/brain/aws021
PMCID: PMC3326251  PMID: 22396393
fronto-parietal network; general intelligence; executive function; voxel-based lesion–symptom mapping
11.  Social neuroscience: the second phase 
doi:10.3389/fnhum.2013.00020
PMCID: PMC3565213  PMID: 23390416
12.  Areas of left perisylvian cortex mediate auditory-verbal short-term memory 
Neuropsychologia  2011;49(13):3612-3619.
A contentious issue in memory research is whether verbal short-term memory (STM) depends on a neural system specifically dedicated to the temporary maintenance of information, or instead relies on the same brain areas subserving the comprehension and production of language. In this study, we examined a large sample of adults with acquired brain lesions to identify the critical neural substrates underlying verbal STM and the relationship between verbal STM and language processing abilities. We found that patients with damage to selective regions of left perisylvian cortex—specifically the inferior frontal and posterior temporal sectors—were impaired on auditory-verbal STM performance (digit span), as well as on tests requiring the production and/or comprehension of language. These results support the conclusion that verbal STM and language processing are mediated by the same areas of left perisylvian cortex.
doi:10.1016/j.neuropsychologia.2011.09.013
PMCID: PMC3209761  PMID: 21945329
Short-term memory; Language; Lesion; Neuropsychology
13.  Fronto-parietal regulation of media violence exposure in adolescents: a multi-method study 
Adolescents spend a significant part of their leisure time watching TV programs and movies that portray violence. It is unknown, however, how the extent of violent media use and the severity of aggression displayed affect adolescents’ brain function. We investigated skin conductance responses, brain activation and functional brain connectivity to media violence in healthy adolescents. In an event-related functional magnetic resonance imaging experiment, subjects repeatedly viewed normed videos that displayed different degrees of aggressive behavior. We found a downward linear adaptation in skin conductance responses with increasing aggression and desensitization towards more aggressive videos. Our results further revealed adaptation in a fronto-parietal network including the left lateral orbitofrontal cortex (lOFC), right precuneus and bilateral inferior parietal lobules, again showing downward linear adaptations and desensitization towards more aggressive videos. Granger causality mapping analyses revealed attenuation in the left lOFC, indicating that activation during viewing aggressive media is driven by input from parietal regions that decreased over time, for more aggressive videos. We conclude that aggressive media activates an emotion–attention network that has the capability to blunt emotional responses through reduced attention with repeated viewing of aggressive media contents, which may restrict the linking of the consequences of aggression with an emotional response, and therefore potentially promotes aggressive attitudes and behavior.
doi:10.1093/scan/nsq079
PMCID: PMC3190206  PMID: 20934985
aggression; violence; functional magnetic resonance imaging; skin conductance response; Granger causality mapping
14.  Reward processing abnormalities in Parkinson disease 
Background
The primary motor cortex is important for motor learning and response selection, functions that require information on the expected and actual outcomes of behavior. Therefore, it should receive signals related to reward and pathways from reward centers to motor cortex exist in primates. Previously, we showed that gamma aminobutyric acid-A(GABAA)-mediated inhibition in motor cortex, measured by paired transcranial magnetic stimulation (TMS), changes with expectation and uncertainty of money rewards generated by a slot machine simulation.
Methods
We examined the role of dopamine in this phenomenon by testing 13 mildly affected Parkinson disease patients, off and on dopaminergic medications, and 13 healthy, age-matched controls.
Results
Consistent with a dopaminergic mechanism, reward expectation or predictability modulated the response to paired TMS in controls, but not in unmedicated patients. A single dose of pramipexole restored this effect of reward, mainly by increasing the paired TMS response amplitude during low expectation. Levodopa produced no such effect. Both pramipexole and levodopa increased risk-taking behavior on the Iowa Gambling Task. However, pramipexole increased risk-taking behavior more in patients showing lower paired TMS response amplitude during low expectation.
Conclusions
These results provide evidence that modulation of motor cortex inhibition by reward is mediated by dopamine signaling and that physiological states in the motor cortex are associated with levels of risk-taking behavior in patients on pramipexole. The cortical response to reward expectation may represent an endophenotype for risk-taking behavior in patients on agonist treatment.
doi:10.1002/mds.23701
PMCID: PMC3150632  PMID: 21538525
Transcranial magnetic stimulation (TMS); dopamine; gambling; motor cortex
15.  Implicit Attitudes in Prosopagnosia 
Neuropsychologia  2011;49(7):1851-1862.
We studied a male with acquired prosopagnosia using a battery of implicit association tests (IATs) to investigate whether observing faces varying by social category would activate the patient’s implicit social biases. We also asked him to categorize faces explicitly by race, gender, and political party. The patient, G.B., was marginally slower to categorize black compared to white faces. He showed congruency effects in the race and celebrity IATs, but not in the gender or political IATs. These results indicate that G.B. possesses an implicit social sensitivity to certain facial stimuli despite an inability to overtly recognize familiar faces. The results demonstrate that social biases can be retrieved based on facial stimuli via pathways bypassing the fusiform gyri. Thus the IAT effect can be added to the list of covert recognition effects found in prosopagnosia.
doi:10.1016/j.neuropsychologia.2011.03.009
PMCID: PMC3100369  PMID: 21414330
prosopagnosia; implicit attitudes; brain lesions; traumatic brain injury; social cognition
16.  Genetic and Clinical Features of Progranulin-Associated Frontotemporal Lobar Degeneration 
Archives of neurology  2011;68(4):488-497.
Objective
To assess the relative frequency of unique mutations and their associated characteristics in 97 individuals with mutations in progranulin (GRN), an important cause of frontotemporal lobar degeneration (FTLD).
Participants and Design
A 46-site International Frontotemporal Lobar Degeneration Collaboration was formed to collect cases of FTLD with TAR DNA-binding protein of 43-kDa (TDP-43)–positive inclusions (FTLD-TDP). We identified 97 individuals with FTLD-TDP with pathogenic GRN mutations (GRN+ FTLD-TDP), assessed their genetic and clinical characteristics, and compared them with 453 patients with FTLD-TDP in which GRN mutations were excluded (GRN− FTLD-TDP). No patients were known to be related. Neuropathologic characteristics were confirmed as FTLD-TDP in 79 of the 97 GRN+ FTLDTDP cases and all of the GRN− FTLD-TDP cases.
Results
Age at onset of FTLD was younger in patients with GRN+ FTLD-TDP vs GRN− FTLD-TDP (median, 58.0 vs 61.0 years; P<.001), as was age at death (median, 65.5 vs 69.0 years; P<.001). Concomitant motor neuron disease was much less common in GRN+ FTLDTDP vs GRN− FTLD-TDP (5.4% vs 26.3%; P<.001). Fifty different GRN mutations were observed, including 2 novel mutations: c.139delG (p.D47TfsX7) and c.378C>A (p.C126X). The 2 most common GRN mutations were c.1477C>T (p.R493X, found in 18 patients, representing 18.6% of GRN cases) and c.26C>A (p.A9D, found in 6 patients, representing 6.2% of cases). Patients with the c.1477C>T mutation shared a haplotype on chromosome 17; clinically, they resembled patients with other GRN mutations. Patients with the c.26C>A mutation appeared to have a younger age at onset of FTLD and at death and more parkinsonian features than those with other GRN mutations.
Conclusion
GRN+ FTLD-TDP differs in key features from GRN− FTLD-TDP.
doi:10.1001/archneurol.2011.53
PMCID: PMC3160280  PMID: 21482928
17.  Orbitofrontal Contributions to Human Working Memory 
Cerebral Cortex (New York, NY)  2010;21(4):789-795.
Although cognitive neuroscience has made remarkable progress in understanding the involvement of the prefrontal cortex in human memory, the necessity of the orbitofrontal cortex for key competencies of working memory remains largely unexplored. We therefore studied human brain lesion patients to determine whether the orbitofrontal cortex is necessary for working memory function, administering subtests of the Wechsler memory scale, the Wechsler adult intelligence scale, and the n-back task to 3 participant groups: orbitofrontal lesions (n = 24), prefrontal lesions not involving orbitofrontal cortex (n = 40), and no brain lesions (n = 54). Orbitofrontal damage was reliably associated with deficits on neuropsychological tests involving the coordination of working memory maintenance, manipulation, and monitoring processes (n-back task) but not on pure tests of working memory maintenance (digit/spatial span forward) or manipulation (digit/spatial span backward and letter–number sequencing). Our findings elucidate a central component of the neural architecture of working memory, providing key neuropsychological evidence for the necessity of the orbitofrontal cortex in executive control functions underlying the joint maintenance, manipulation, and monitoring of information in working memory.
doi:10.1093/cercor/bhq153
PMCID: PMC3059885  PMID: 20724371
lesion data; orbitofrontal cortex; prefrontal cortex; working memory
18.  A Need for Improved Training Interventions for the Remediation of Impairments in Social Functioning following Brain Injury 
Journal of Neurotrauma  2011;28(2):319-326.
Abstract
Social functioning deficits are a prominent feature of many neurological and psychiatric conditions, and may include disruption in the acquisition or application of basic or complex social skills. Such disturbances are often resistant to treatment, and individuals with such conditions are often faced with lifelong difficulties in maintaining personal relationships, employment, and independent living. In recent years, a number of psychosocial treatments have been developed to address this growing problem. In this article, we review studies investigating the use of psychosocial training interventions in individuals with acquired brain injuries, which frequently require intervention for impairments in cognitive and social functioning. We then discuss limitations of these studies and highlight specific areas in which such treatments might be improved in the future.
doi:10.1089/neu.2010.1523
PMCID: PMC3037813  PMID: 21121768
brain injury; neuroplasticity; rehabilitation; social cognition; social skills
19.  Impairment of prosocial sentiments is associated with frontopolar and septal damage in frontotemporal dementia 
NeuroImage  2010;54(2):1735-1742.
Poets and philosophers have long acknowledged moral sentiments as key motivators of human social behavior. Prosocial sentiments, which include guilt, pity and embarrassment, enable us to care about others and to be concerned about our mistakes. Functional imaging studies have implicated frontopolar, ventromedial frontal and basal forebrain regions in the experience of prosocial sentiments. Patients with lesions of the frontopolar and ventromedial frontal areas were observed to behave inappropriately and less prosocially, which could be attributed to a generalized emotional blunting. Direct experimental evidence for brain regions distinctively associated with moral sentiment impairments is lacking, however. We investigated this issue in patients with the behavioral variant of frontotemporal dementia, a disorder in which early and selective impairments of social conduct are consistently observed. Using a novel moral sentiment task, we show that the degree of impairment of prosocial sentiments is associated with the degree of damage to frontopolar cortex and septal area, as assessed with 18-Fluoro-Deoxy-Glucose-Positron Emission Tomography, an established measure of neurodegenerative damage. This effect was dissociable from impairment of other-critical feelings (anger and disgust), which was in turn associated with dorsomedial prefrontal and amygdala dysfunction. Our findings suggest a critical role of the frontopolar cortex and septal region in enabling prosocial sentiments, a fundamental component of moral conscience.
doi:10.1016/j.neuroimage.2010.08.026
PMCID: PMC2997153  PMID: 20728544
frontopolar cortex; prefrontal cortex; subgenual; septal area; amygdala; orbitofrontal cortex; moral sentiment; emotion
20.  Developmental effects of aggressive behavior in male adolescents assessed with structural and functional brain imaging 
Aggressive behavior is common during adolescence. Although aggression-related functional changes in the ventromedial prefrontal cortex (vmPFC) and frontopolar cortex (FPC) have been reported in adults, the neural correlates of aggressive behavior in adolescents, particularly in the context of structural neurodevelopment, are obscure. We used functional and structural magnetic resonance imaging (MRI) to measure the blood oxygenation level-depended signal and cortical thickness. In a block-designed experiment, 14–17-year old adolescents imagined aggressive and non-aggressive interactions with a peer. We show reduced vmPFC activation associated with imagined aggressive behavior as well as enhanced aggression-related activation and cortical thinning in the FPC with increasing age. Changes in FPC activation were also associated with judgments of the severity of aggressive acts. Reduced vmPFC activation was associated with greater aggression indicating its normal function is to exert inhibitory control over aggressive impulses. Concurrent FPC activation likely reflects foresight of harmful consequences that result from aggressive acts. The correlation of age-dependent activation changes and cortical thinning demonstrates ongoing maturation of the FPC during adolescence towards a refinement of social and cognitive information processing that can potentially facilitate mature social behavior in aggressive contexts.
doi:10.1093/scan/nsp036
PMCID: PMC3023076  PMID: 19770220
ventromedial prefrontal cortex; frontopolar cortex; fMRI; cortical thickness; neurodevelopment; trait anger
21.  Identifying temporal and causal contributions of neural processes underlying the Implicit Association Test (IAT) 
The Implicit Association Test (IAT) is a popular behavioral measure that assesses the associative strength between outgroup members and stereotypical and counterstereotypical traits. Less is known, however, about the degree to which the IAT reflects automatic processing. Two studies examined automatic processing contributions to a gender-IAT using a data driven, social neuroscience approach. Performance on congruent (e.g., categorizing male names with synonyms of strength) and incongruent (e.g., categorizing female names with synonyms of strength) IAT blocks were separately analyzed using EEG (event-related potentials, or ERPs, and coherence; Study 1) and lesion (Study 2) methodologies. Compared to incongruent blocks, performance on congruent IAT blocks was associated with more positive ERPs that manifested in frontal and occipital regions at automatic processing speeds, occipital regions at more controlled processing speeds and was compromised by volume loss in the anterior temporal lobe (ATL), insula and medial PFC. Performance on incongruent blocks was associated with volume loss in supplementary motor areas, cingulate gyrus and a region in medial PFC similar to that found for congruent blocks. Greater coherence was found between frontal and occipital regions to the extent individuals exhibited more bias. This suggests there are separable neural contributions to congruent and incongruent blocks of the IAT but there is also a surprising amount of overlap. Given the temporal and regional neural distinctions, these results provide converging evidence that stereotypic associative strength assessed by the IAT indexes automatic processing to a degree.
doi:10.3389/fnhum.2012.00320
PMCID: PMC3510688  PMID: 23226123
event-related brain potentials; traumatic brain injuries; EEG coherence; implicit association test; automaticity; gender stereotypes; extra-striate visual cortex; prefrontal cortex
22.  Novel missense mutation in Charged Multivesicular body Protein 2B in a patient with Frontotemporal Dementia 
Frontotemporal Dementia (FTD) is the second major cause of dementia in persons under the age of 65 after Alzheimer’s disease (AD). FTD is clinically, pathologically and genetically heterogeneous and has been associated with mutations in different genes located on chromosomes 17, 9 and 3. In our study we report a novel heterozygous g.26218G>A variant in exon 6 of Charged Multivesicular body Protein 2B (CHMP2B), predicted to cause the amino acid change p.Ser187Asn, in one patient diagnosed with FTD. We were not able to determine the mode of inheritance of the mutation since we did not have access to the genetically informative family members of the proband; those who were screened did not carry the variant. We didn’t find this variant in 273 Caucasian controls while we did find it in 6 of 94 African American controls. Most of the mutations in CHMP2B which are considered pathogenic lead to partial deletion of the C-terminus region of CHMP2B protein. Based on previous reports and on our current data, missense mutations seem unlikely to be pathogenic. The pathogenicity of CHMP2B mutations requires further investigation.
doi:10.1097/WAD.0b013e3181df20c7
PMCID: PMC2974047  PMID: 20592581
dementia; FTD; CHMP2B; gene; missense mutation
23.  Behavioral norms for condensed moral vignettes 
Moral judgment is an evaluation of the actions and character of a person made with respect to societal norms. Although many types of vignettes have been used in previous studies on moral beliefs and judgment, what is missing is a set of standardized common vignettes based in real life. The goal of this study was to provide researchers with stimuli that have values on several dimensions pertaining to moral judgment and whose underlying components are known. These values will allow researchers to select stimuli based on standardized ratings rather than on the results of pilot studies, while avoiding the limitations of the classic, abstract moral scenarios. Our study was composed of three phases, (i) collecting and shortening the vignettes, (ii) obtaining ratings of the vignettes on several dimensions including emotional intensity, degree of social norm violation, and level of harm or benefit caused and (iii) determining the underlying components of the vignettes by performing a factor analysis. We found three components that accounted for most of the variance: norm violation, social affect and intention. The resulting vignettes can be used in future parametric studies on moral judgment in behavioral, neuropsychological and functional imaging experiments.
doi:10.1093/scan/nsq005
PMCID: PMC2999756  PMID: 20154053
moral cognition; moral judgment; norms
24.  BDNF Polymorphism Predicts General Intelligence after Penetrating Traumatic Brain Injury 
PLoS ONE  2011;6(11):e27389.
Neuronal plasticity is a fundamental factor in cognitive outcome following traumatic brain injury. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, plays an important role in this process. While there are many ways to measure cognitive outcome, general cognitive intelligence is a strong predictor of everyday decision-making, occupational attainment, social mobility and job performance. Thus it is an excellent measure of cognitive outcome following traumatic brain injury (TBI). Although the importance of the single-nucleotide polymorphisms polymorphism on cognitive function has been previously addressed, its role in recovery of general intelligence following TBI is unknown. We genotyped male Caucasian Vietnam combat veterans with focal penetrating TBI (pTBI) (n = 109) and non-head injured controls (n = 38) for 7 BDNF single-nucleotide polymorphisms. Subjects were administrated the Armed Forces Qualification Test (AFQT) at three different time periods: pre-injury on induction into the military, Phase II (10–15 years post-injury, and Phase III (30–35 years post-injury). Two single-nucleotide polymorphisms, rs7124442 and rs1519480, were significantly associated with post-injury recovery of general cognitive intelligence with the most pronounced effect at the Phase II time point, indicating lesion-induced plasticity. The genotypes accounted for 5% of the variance of the AFQT scores, independently of other significant predictors such as pre-injury intelligence and percentage of brain volume loss. These data indicate that genetic variations in BDNF play a significant role in lesion-induced recovery following pTBI. Identifying the underlying mechanism of this brain-derived neurotrophic factor effect could provide insight into an important aspect of post-traumatic cognitive recovery.
doi:10.1371/journal.pone.0027389
PMCID: PMC3210804  PMID: 22087305
25.  The Role of the Met66 Brain-Derived Neurotrophic Factor Allele in the Recovery of Executive Functioning after Combat-Related Traumatic Brain Injury 
Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, promotes survival and synaptic plasticity in the human brain. The Val66Met polymorphism of the BDNF gene interferes with intracellular trafficking, packaging, and regulated secretion of this neurotrophin. The human prefrontal cortex (PFC) shows lifelong neuroplastic adaption implicating the Val66Met BDNF polymorphism in the recovery of higher-order executive functions after traumatic brain injury (TBI). In this study, we examined the effect of this BDNF polymorphism on the recovery of executive functioning after TBI. We genotyped a sample of male Vietnam combat veterans consisting of a frontal lobe lesion group with focal penetrating head injuries and a non-head-injured control group for the Val66Met BDNF polymorphism. The Delis–Kaplan Executive Function System as a standardized psychometric battery was administrated to examine key domains of executive functions. The results revealed that the Met allele but not the hypothesized Val allele promotes recovery of executive functioning. Overall, the Met66 carriers in the lesion group performed as well as the Met66 carriers in the control group. The Met66 allele accounted for 6.2% of variance for executive functioning independently of other significant predictors including preinjury intelligence, left hemisphere volume loss, and dorsolateral PFC volume loss. The findings point to different mechanisms of the Val66Met BDNF gene in complex phenotypes under normal and pathological conditions. A better understanding of these mechanisms could be instrumental in the development and application of effective therapeutic strategies to facilitate recovery from TBI.
doi:10.1523/JNEUROSCI.1399-10.2011
PMCID: PMC3195417  PMID: 21228168

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